Pulmonary and systemic vascular effects of SRS-A blockade in conscious lambs

There is preliminary evidence suggesting that hypoxic pulmonary vasoconstriction may be mediated by slow-reacting substance of anaphylaxis (SRS-A), which is comprised of leukotrienes C4, D4, and E4. We studied the effects of the SRS-A antagonist FPL 57231 (FPL) on the hypoxic pulmonary vasoconstrictor response and on systemic vascular resistance in awake, chronically instrumented young lambs. Two other studies were performed to ascertain whether FPL's vasodilation was specific for hypoxic pulmonary vasoconstriction: the effect of FPL infusion in pulmonary and systemic vascular resistance was measured in six normoxic lambs, and the effect of FPL on 5-hydroxytryptamine (5-HT)-mediated vasoconstriction was determined. In seven lambs, mean pulmonary arterial pressure was 21 mmHg in room air and 28 mmHg in hypoxia (Po2 = 43 Torr). During hypoxia, FPL infusion (2 mg X kg-1 X min-1) reversibly decreased pulmonary arterial pressure to 15 mmHg; pulmonary arteriolar resistance also fell below normoxia levels with FPL. FPL also caused a fall in aortic pressure and systemic vascular resistance in these hypoxic lambs, but the decrease in systemic resistance was less than the fall in pulmonary resistance. beta-Adrenergic blockade using propranolol (1 mg/kg) did not affect the pulmonary vasodilation caused by FPL. In six normoxic lambs, FPL infusion also significantly decreased pulmonary and systemic vascular resistance (29% in each case). These data are consistent with the idea that leukotrienes may be involved in adjusting both pulmonary and systemic vascular tone, but further work is necessary to establish whether FPL's vasodilation is mediated via its leukotriene antagonism or is a nonspecific effect of FPL.